Parasites characteristically show strong specificity to particular hosts, but the genetic basis for this host specificity is poorly understood. In Schistosoma mansoni, one of three medically important schistosome species infecting humans, elegant experimental work demonstrates that both chemical recognition of the intermediate snail host and survival of parasites within snails follow a simple Mendelian pattern of inheritance. While Egyptian parasites show strong chemical recognition of the sympatric snail Biomphalaria alexandrina, Brazilian parasites show no specificity and are attracted to even non-vector snail hosts. Similarly, while both Egyptian and Brazilian parasites infect and proliferate in their sympatric snail hosts, F1 hybrids develop only in S. American B. glabrata snails. New molecular tools allow us to determine the parasite genes that determine host specificity in this host-parasite system, providing a means to understand key molecular interactions between parasites and snail vector. Using R21 funding we have (a) developed a 5 cM linkage map for S. mansoni, and (b) demonstrated the utility of linkage mapping by identifying a strong QTL (LOD = 21) for oxamniquine resistance to a short region of chr 6. We now propose to exploit the genetic map, together with the recently published genome sequence of S. mansoni identify the genome region(s) that underlie host specificity in the S. mansoni - Biomphalaria system. Host specificity involves two components (a) chemical location of snails by miracidia and (b) penetration and clonal proliferation of schistosome larvae within snails. For both traits, we will conduct genetic crosses between Brazilian and Egyptian S. mansoni, using snail infections with single miracidia to generate single genotype infections in snails. We will quantify chemical recognition behavior of single F2 miracidia to both B. glabrata and B. alexandrina, and then genotype individual miracidia using SNPs spaced at ~4 cM (2Mb) intervals across the S. mansoni genome to identify QTLs for this trait. Genetic mapping of survival and clonal proliferation within the snail host is not possible using classical linkage mapping methods, because parasites that do not grow within snails cannot be genotyped. We will therefore use extreme QTL (X-QTL) methods, developed by malaria and yeast geneticists, to examine allele frequencies of F2 cercariae emerging from either B. glabrata or B. alexandrina snails. At the causative loci, we expect alleles from the Egyptian S. mansoni parent to be overrepresented in F2 cercariae emerging from B. alexandrina relative to those emerging from B. glabrata. Hence locus specific deviation from normal Mendelian segregation allows QTL location. Having fine mapped QTL regions for both traits, we will use RNAi disruption of gene function or retroviral based transfection to aid identification of causative loci. Understanding the genetic and molecular basis of host specificity in the S. mansoni - Biomphalaria system is critical for control efforts that aim to disrupt this step in the parasite lifecycle and provides a key to understanding evolution of host specificity in the most important of the human helminth parasites.